Low-frequency, mild-gradient chronic intermittent hypoxia still induces liver fibrogenesis in mice on a high-fat diet

Abstract

The fibrogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD) may progress when complicated by obstructive sleep apnea (OSA). Studies using animal models have shown that high-frequency intermittent hypoxia (IH) exposure, which resembles human OSA, accelerates liver fibrosis in fatty liver. This study highlights that low-frequency, mild-gradient intermittent hypoxia (IH) can exacerbate fibrogenesis in fatty liver disease, even without significantly raising markers of liver injury or insulin resistance. Using a mice model on a high-fat diet (HFD), we found that while routine liver tests (e.g., ALT, AST) and cholesterol levels remained comparable between HFD mice exposed to room air (RA) versus those exposed to chronic intermittent hypoxia (CIH), indicators of liver fibrosis and oxidative stress were elevated in the latter group. This suggests that even low-frequency, mild-gradient IH can increase oxidative stress and fibrotic activity within the liver, primarily through the upregulation of specific markers like ICAM-1 and osteopontin (OPN), which may play a role CIH-induced liver inflammation and fibrosis in fatty liver. In conclusion. Our study further notes that these hypoxia-related changes occurred without significantly worsening systemic insulin resistance, focusing attention on localized liver impacts rather than global metabolic disruptions. The findings underscore the potential role of oxidative stress and specific cytokines in the progression of liver fibrosis in MASLD, especially when complicated by conditions that introduce IH.